Hirano bodies are cytoplasmic inclusions described in association with the cellular pathology of aging, and a variety of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. Since previous studies of Hirano bodies have been performed on preserved clinical brain samples, there is no direct information on the effects of Hirano bodies on cell physiology, aging, or neurodegenerative disease. A model for formation of Hirano bodies in cultured cells has recently been described. The model Hirano bodies are indistinguishable from Hirano bodies in pathology samples in all criteria described by prior ultrastructural and immunohistochemical studies of Hirano bodies. Since Hirano bodies are a widespread type of cytoplasmic protein inclusion associated with numerous significant diseases, it is important to determine their effects on the physiology of neuronal cells. The aim of this project is to test the following 3 alternative hypotheses: 1) Hirano bodies promote/ reflect cellular pathology and toxicity; 2) Hirano bodies are adaptive structures that promote survival of neuronal cells under stresses that are known to contribute to neurodegenerative diseases; or 3) Hirano bodies have no effect on survival of neuronal cells under physiological stress. The effect of Hirano bodies on the neurotoxicity of 5 stresses implicated in the pathology of neurodegenerative disease will be determined. These 5 stresses are: 1) oxidative stress that damages protein, lipid, and nucleic acid; 2) glutamate excitotoxicity that initiates prolonged elevation of intracellular calcium; 3) ischemia (ATP depletion) most commonly associated with stroke or hypoxia; 4) Ab peptide, the leading candidate for initiation of the pathology of Alzheimer's disease; and 5) the intracellular cytoplasmic domain of the amyloid precursor protein (AICD) that can initiate programmed cell death. The results will provide a direct test of the hypothesis that Hirano bodies affect the survival of neuronal cells challenged with physiological stress by promoting either the death or the survival of neurons in disease. Elucidation of the potential roles of Hirano bodies in disease is prerequisite to possible development of animal models, interventions, or therapies.